Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Noninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer's Disease.

BACKGROUND: Patients with Alzheimer's disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD. OBJECTIVE: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD. METHODS: In this study, we used the magnetic resonance imaging (MRI) data from the OVERTURE study (NCT03556280), a randomized, controlled, clinical trial in which active treatment participants received daily, non-invasive, combined visual and auditory, 40 Hz stimulation for six months. A subset of OVERTURE participants who meet the inclusion criteria for detailed white matter (N = 38) and myelin content (N = 36) assessments are included in the analysis. White matter volume assessments were performed using T1-weighted MRI, and myelin content assessments were performed using T1-weighted/T2-weighted MRI. Treatment effects on white matter atrophy and myelin content loss were assessed. RESULTS: Combined visual and auditory gamma-sensory stimulation treatment is associated with reduced total and regional white matter atrophy and myelin content loss in active treatment participants compared to sham treatment participants. Across white matter structures evaluated, the most significant changes were observed in the entorhinal region. CONCLUSIONS: The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss. Furthermore, the entorhinal region MRI outcomes may have significant implications for early disease intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex.

Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients.

Pathological proteins contributing to Alzheimer's disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT03556280.